The dopaminergic system is clearly implicated as important in mediating the effects of many drugs of abuse, as well as Parkinsons disease, and schizophrenia. Our studies have as their goals the determination of the functional significance of the dopamine system in normal functioning, as well as how it acts to subserve drug abuse. One specific objective is to better characterize the pharmacology of the various subtypes of CNS dopamine receptors. Included in this goal is the identification of drugs that act selectively and with high efficacy. In many cases the pharmacological tools for the study of these receptor subtypes in vivo and in vitro are limited. As a result, one further goal is the discovery of new synthetic entities that will allow analysis of the pharmacology of these dopamine receptor subtypes. These studies have indicated that: (1) Many of the known dopamine D2 agonists also have affinity for dopamine D3 receptors. Studies are being conducted in order to discover drugs that are selective for either D2 or D3 receptors. Recent studies have focused on the putative D3 receptor agonists 7-OH-DPAT and PD 128,907. These "preferential" D3 agonists produced subjective effects that were similar, based on the spectrum of compounds that substituted for them, in rats trained to discriminate these drugs from saline injections. Because PD 128,907 has been suggested to be a highly selective D3 ligand, its pharmacological similarity to 7-OH-DPAT is surprising. The putative selective D2 agonist, U91356A, fully substituted for both PD 128,907 and 7-OH-DPAT, suggesting that the subjective effects of both of these compounds are mediated by actions at D2 dopamine receptors. This results may be related to the relatively lower level of D3 receptors in the CNS compared to D2 receptors. Interestingly, cocaine failed to substitute for either 7-OH-DPAT or PD 128,907, suggesting that the complexity of actions of cocaine render its subjective effects substantially different from those of direct acting agonists. (2) Studies of the actions of several novel dopamine D3 and D4 receptor antagonists are in progress. These studies will provide information on the roles of these receptor systems in tonic regulation of behavioral processes. Surprisingly, none of the D4 antagonists studied to date have had profound behavioral effects. These results contrast with the potent activity of D1 and D2 antagonists. The activity of these latter antagonists suggests that significant dopaminergic tone at D1 and D2 receptors is interrupted by these antagonists, leading to their behavioral activity.